Interrogating Intratumoral Heterogeneity and Therapeutic Resistance
Tumor evolution, driven by intratumor heterogeneity (ITH) and phenotypic plasticity, is a primary cause of therapeutic failure. The Bailey Laboratory investigates the genetic and non-genetic mechanisms sustaining this diversity. Recent work from the Bailey and Corbo labs, published in Nature, has identified extrachromosomal DNA (ecDNA) as a major source of genomic heterogeneity and adaptability in PDAC. ecDNAs are small, circular DNA elements that exist outside of the chromosomes and can carry key oncogenes. The study found that ecDNA is surprisingly common in pancreatic tumors and is a primary mechanism for achieving high-level amplification of the oncogene MYC. Unlike chromosomally-located genes, ecDNAs can accumulate to hundreds of copies per cell, driving extreme and variable levels of oncogene expression. This creates profound intratumor heterogeneity, where different subclones within the same tumor harbor varying ecDNA copy numbers, enabling a "bet-hedging" strategy for survival. This dynamic copy number allows cancer cells to rapidly and reversibly adapt to microenvironmental pressures. For example, under stress conditions such as the removal of WNT growth signals, cells with high levels of ecDNA-driven MYC can become more autonomous and self-sufficient.
This high oncogene dosage also affects cell morphology, with the highest MYC levels correlating with more aggressive, squamous-like phenotypes. This work identifies a novel and critical genetic engine of heterogeneity and therapeutic adaptation in PDAC.
ITH may also drive therapeutic failure through the emergence of drug-tolerant "persister" cells (DTPs). DTPs are a rare, often slow-cycling subpopulation of cancer cells that survive initial treatment without harboring classic genetic resistance mutations. This transient, reversible state allows them to persist under therapeutic pressure and can eventually lead to tumor relapse.
Recent work from the Bailey laboratory has identified distinct persister cell phenotypes that contribute to poor outcomes in PDAC patients following neoadjuvant chemotherapy. Analysis of patient samples before and after treatment revealed that chemotherapy enriches pre-existing persister cells that co-express markers of both Classical (GATA6) and Basal-like (KRT17) subtypes. The persistence of these GATA6Hi and KRT17Hi cells after treatment with the mFOLFIRINOX regimen was significantly associated with poor survival. The research identified a key mechanism for this tolerance: the expression of Cytochrome P450 3A (CYP3A). This enzyme metabolizes the prodrug irinotecan, a key component of mFOLFIRINOX, into an inactive form, effectively neutralizing the treatment. This discovery of CYP3A-expressing drug- tolerant phenotypes in residual disease provides a critical insight into non-genetic resistance mechanisms and may inform the selection of more effective adjuvant therapies. To dissect this complexity, the lab is utilising single-cell multiomic approaches. This technology provides a high-resolution view of the tumor ecosystem, allowing the lab to distinguish malignant cells from the tumor microenvironment (TME), identify rare drug-resistant populations like persister cells, and map the cellular communication networks that drive resistance.
